In order to prevent central nervous system injury in the newborn resulting from unconjugated hyperbilirubinemia (kernicterus), the mechanisms responsible for physiologic jaudice in the neonate and for transfer of bilirubin from plasma into the brain must be more fully understood. Extensive work from this laboratory and by others in recent years has indicated that physiologic jaudice results from a complex interaction between increased bilirubin load presented to the newborn liver and decreased hepatic conjugation and uptake of bilirubin. Part I of the proposed studies seeks to define the relative contributions of enteric bilirubin absorption and de novo synthesis of bilirubin during maturation in the newborn rhesus monkey. Factors which may enhance or prevent enteric bilirubin absorption will also be examined. In a separate set of monkey studies, maturation of hepatic uptake of bilirubin will be examined in order to define "relative hepatic uptake deficiency: in the newborn and the underlying mechanisms. A third study in the newborn monkey will examine the formation of non-glucuronide conjugates of bilirubin. In a second set of studies, the mechanisms responsible for the transfer of bilirubin into the central nervous system will be examined through development of a model for kernicterus which will be utilized for assessment of a series of factors believed to enhance the development of bilirubin encephalopathy. Several new concepts for the pathogenesis of kernicterus will be investigated, including the role of certain unesterified fatty acids in the transport of bilirubin in plasma and into the brain. Morphologic, histochemical and mitochondrial respiration techniques will be used to evaluate the kernicterus model. The ultimate aim of this proposal is to achieve sufficient understanding of the mechanisms of bilirubin accumulation in plasma and brain to permit develop of rational methods for therapeutic intervention to prevent bilirubin encephalopathy in the human neonate.